She Has Her Mother's Laugh: The Powers, Perversions, and Potential of Heredity (33 page)

“
I am very proud of my 2.8% Neanderthal DNA,” someone named Gayle wrote in 2011. “Neanderthals had larger brains than modern humans, cared for the sick and elderly, buried their dead, wore jewelry in the form of painted sea shells, crafted musical instruments, and gave us hybrid vigor.”

Replying to Gayle, another commenter named Lee Ann wondered if Neanderthal DNA might explain the look of her family. “I haven't been tested, although I should, out of curiosity,” she wrote. “My genealogy has me as the 27th gr granddaughter of William the Conqueror, the Saxon that made England Anglo Saxon. Every generation in the modern family of the past 200 years has one or two tall, heavy boned people, surrounded by average height and weight. My brother was 5'10”, 165 pounds. I am 6' tall, big boned along with carrying some extra weight. I am hairier than he is, he cannot grow a beard, I could grow a beard on my legs alone.”

Ancient DNA experts had mixed feelings about this new Neanderthal mania. They were happy to see all the enthusiasm over their research, but they also didn't like the pretzels into which it was getting stretched. The 23andMe test, for example, was based only on the 2010 rough draft of the Neanderthal genome. Only later did Pääbo and his colleagues discover that a Neanderthal toe bone from Siberia was packed with DNA—so much DNA that they were able to reconstruct the entire genome with high accuracy. In 2014, the researchers compared this high-quality Neanderthal genome to more than a thousand human genomes. It was like switching a microscope to a far more powerful lens.

Africans turned out to have between 0.08 and 0.34 percent Neanderthal DNA, likely from the migration of people from the Near East to the continent. Non-Africans had ancestry varying from just over 1 percent to 1.4 percent. That was a far narrower window than the 1 to 4 percent in the original estimates. And within each population, the variation from person to person was far smaller. Central Europeans had an average of 1.17 percent Neanderthal DNA, plus or minus only 0.08 percent. When the Neanderthal researchers published their analysis, they went out of their way to take a
swipe at the 23andMe test. For the most part, the researchers said, the test only delivered “
statistical noise.”

Even if some people actually did have twice as much Neanderthal DNA than others, that wouldn't somehow make them more “Neanderthal,” as if Neanderthalness were a spice sprinkled into our genomic soup. Living people who carry Neanderthal DNA have thousands of genetic fragments scattered by meiosis throughout their chromosomes. Most of those fragments probably do nothing at all. Our protein-coding genes make up only about 1 percent of the human genome. It's possible that a few percent more is made up of genes that encode important RNA molecules. Some additional DNA may be important to us as millions of tiny genetic switches, where proteins known as transcription factors can attach to turn genes on and off. But it's likely that the vast majority of human DNA has no function. It's just along for the ride. Inheriting a Neanderthal piece of this so-called junk DNA instead of the human version should make no difference to us.

Some of the Neanderthal DNA we inherit can potentially make a difference if it contains important genes or stretches of DNA that help turn genes on and off. But from one person to the next, the fragments of Neanderthal DNA that survive in the genome are different. Whatever the impact of our Neanderthal inheritance may turn out to be, it will depend on the particular genes each of us inherit.

To find out what my Neanderthal DNA meant to me, I enlisted Adam Siepel, who by then had been studying ancient genomes for several years at Cold Spring Harbor. He was intrigued by the request, admitting that he had never been a big fan of the 23andMe Neanderthal test.

“They just give you a number,” he said. “They don't tell you
where
you're Neanderthal.”

I arranged for Siepel to get my genome, and then he and two of his colleagues, Melissa Jane Hubisz and Ilan Gronau, set about analyzing it. They used a statistical method they had invented a few years beforehand that can detect mixtures of different kinds of inherited DNA that might go overlooked by other methods.

First the scientists chopped up my genome into thousands of sections, each a million bases long. They then compared each of those sections to corresponding ones in people of European, Asian, and African descent. They also compared my sections of DNA to those of Neanderthals and chimpanzees, the closest living species related to humans. Siepel and his colleagues tested out many evolutionary trees to see which accounted best for all these similarities and differences. They drew trees with different sets of branches and also investigated scenarios in which DNA slipped from one branch to another, thanks to interbreeding. “It builds a coherent model that has to explain everything,” Siepel said.

It took days for a computer to churn through all the data, explore all the possibilities, and finally produce an answer. To walk me through the results, Hubisz joined Siepel and me in his office while Gronau, calling in from Israel, peered down at us from a video screen.

“You're definitely pushing us into a new area,” Siepel said. “It's actually a little addictive once you start.”

Together, they unveiled my genealogical tree, reaching back over half a million years. My genome shared a close ancestry with those of other living Europeans. Beyond Europe, they found that Asians were my closest relatives, as a result of the expansion of humans out of Africa. They compared my genome to a Southern African hunter-gatherer's and estimated we could trace our ancestry back to a common ancestral population that existed over 100,000 years ago. On my genealogical tree, I could see Neanderthals on a far more distant branch, splitting off hundreds of thousands of years earlier.

But some of the DNA that Siepel and his colleagues analyzed didn't travel obediently down these branches. Some had jumped from Neanderthals into humans. Each of the humans outside of Africa that Siepel, Gronau, and Hubisz studied had ended up with a different vestige of Neanderthal DNA.

To show me mine, Hubisz opened up a browser on the monitor. Long black bars marked places where one copy of a chromosome carried DNA from Neanderthals. In some regions, I had inherited Neanderthal DNA from both my mother and father. The largest of those doubly inherited
regions spans 189,871 bases. When Hubisz tallied the number of stretches that were 10,000 bases or longer, she ended up with over a thousand.

Some of those spans didn't contain a gene or any other stretch of DNA with a known function. But some of them had promise. “I have a list of interesting regions,” Siepel said, pulling out a piece of paper. “There's a lot I don't know about these, but here are some that I've flagged.”

One segment contained a gene called DSCF5, for example, that has been linked to coronary artery disease. “We can click on a few others that I found,” Siepel said. He threw out names of other genes—CEP350, GPATCH1, and PLOD2.

“Catchy name,” he muttered.

Siepel might be able to name my Neanderthal genes, but he couldn't say which Neanderthal I inherited them from. He couldn't say if it was a male or female Neanderthal, or when that Neanderthal lived, or where. He and other researchers were still just trying to make out the broad outlines of Neanderthal interbreeding. As best they could tell, Neanderthals and humans interbred many times, over a period that may have stretched over 200,000 years.

The earliest hints of interbreeding came to light in 2017. Researchers studying the DNA of European Neanderthals determined that their mitochondria came from an ancient human woman who lived more than 270,000 years ago. It's possible that early members of
Homo sapiens
made their way from northern Africa to southern Europe, where they interbred with the Neanderthals there. If this encounter did happen, those early humans must have vanished, leaving behind only their mitochondria in later generations of Neanderthals.

Siepel and his colleagues have found more evidence of human DNA in Neanderthals more than 100,000 years ago. The fossil record offers hints of where this encounter took place: in the Near East. On the coast of Israel, there is a place called Mount Carmel. Inside its caves, scientists have found the fossils of both Neanderthals and modern humans. The Neanderthals lived in the region from at least 200,000 years ago. Modern humans make a brief appearance at Mount Carmel about 100,000 years ago, and then the
Neanderthals return for another 50,000 years before giving way for good to modern humans. It's possible that the 100,000-year-old humans of Mount Carmel belonged to a brief expansion out of Africa. Before they vanished, they may have contributed their own DNA to Neanderthals.

The DNA of living humans documents more recent encounters, after humans expanded successfully out of Africa sometime between 50,000 and 80,000 years ago. In a 2016 study,
Joshua Akey and his colleagues at the University of Washington found different patterns of Neanderthal DNA in different groups of people, suggesting that the interbreeding happened in at least three separate episodes.

The first took place not long after modern humans came back to the Near East. This was before non-Africans split into today's major lineages, and so the DNA from this first mingling can be found in all non-African populations. The ancestors of people who live in Australia and New Guinea then split from the rest of non-Africans and moved east along the coast of Asia. The second interbreeding with Neanderthals happened after that split, and today the DNA from that contact can be found in Europeans and East Asians but not in New Guinea or Australia. Finally, after Europeans split from the ancestors of East Asians, Neanderthals bred a third time, with the ancestors of East Asians.

Of course, a study like Akey's has its limits. It can't tell us about other interbreeding that didn't leave any DNA behind in living humans. Nor can it offer all the cinematic details about how the mating took place. Were Neanderthal males having sex with modern human females, or was it the reverse? Did people willingly cross into new societies to raise their children, or were they slaves? For now, we can only craft the different stories we might tell, depending on what the answers to those questions would be.

But the laws of heredity can let us know some things about our Neanderthal inheritance. The children of Neanderthals and humans got half of their DNA from each kind of human. At least some of them must have been welcomed into modern human groups. They must have been cared for and nurtured. They must have gotten the opportunity to have children of their own. Our own DNA is proof.

If those hybrids mated with modern humans, their children would have inherited a quarter of their DNA from a Neanderthal grandparent. Their Neanderthal DNA would be chopped up and shuffled with the DNA of their other grandparents. Over future generations, meiosis split up the Neanderthal DNA into still smaller segments.

Some ancient human fossils turn out to have as much as 6 to 9 percent Neanderthal DNA. Over time, the average amount dwindled. One plausible explanation for that decline is that most Neanderthal DNA is bad for our health. Inheriting a Neanderthal version of a gene may cause people to have fewer children—either because they're less likely to survive to childbearing age, or because they become less fertile. It may be no coincidence that
Neanderthal genes that play a role in reproduction are especially rare in humans today. As future generations of humans inherit Neanderthal DNA, some of it may continue to disappear.

But some Neanderthal DNA seems to have endured for tens of thousands of years because it gave our ancestors some benefit. I've discovered that my genome, for example, includes some Neanderthal versions of genes that help fight infections. I'm hardly alone:
Neanderthal immune genes are more common in living humans than many other classes of genes.

Once they slipped into the modern human gene pool, these genes appear to have become more widespread with time. Our immune system genes are some of the fastest-evolving parts of our genome, because they need to keep up with the rapid evolution of the parasites that are trying to evade our defenses. People who live in malaria-prone regions have evolved new defenses against the parasites in just the past few thousand years. When early Africans moved onto other continents, they may have encountered a number of diseases for the first time. Neanderthals, on the other hand, had been adapting to those medical challenges for hundreds of thousands of years. Borrowing immune system genes from Neanderthals could have been a quick way to get better odds of surviving in their new home.

One of the most startling revelations about my own heredity came up toward the end of my visit to Cold Spring Harbor. After running through all his results, Gronau said something so casually that I almost missed it.

“There is some Denisovan gene flow in Carl's genome,” he said.

I sat up straight. “What?”

“You have a tiny bit, which is more than I see in the other genomes that I've tried,” Gronau said.

In 2009, a Russian researcher sent Svante Pääbo a nondescript chip of bone from a pinky. It had come to light during a dig in a Siberian cave called Denisova. There was no reason to expect anything interesting from the chip, but Pääbo's student Johannes Krause discovered that it was actually packed with DNA. While much of that DNA belonged to bacteria that had invaded the bone long after death, there was also a lot that looked humanlike. Krause assumed it would either be Neanderthal or modern human DNA. But when he inspected it closely, it turned out to be neither. It belonged to another extinct human. In honor of the cave where it was found, Pääbo and his colleagues named these phantom people
the Denisovans.

In the next few years, Pääbo and his colleagues tested out other fossils for Denisovan DNA and managed to find some more from
molars dug up in the same Siberian cave. The scientists cannot look at Denisovan skeletons to compare their anatomy to ours. They're left in the strange situation of knowing a group of extinct human relatives almost entirely from their DNA.